When the first immunotherapy drug, ipilimumab (Yervoy), was FDA approved in 2011, immunotherapy was hailed as a "breakthrough" in cancer treatment. This much-anticipated new therapy harnessed the power of the body's immune system to fight cancer. Fast forward to today, and, unfortunately, only a minority of cancer patients genuinely benefit from immunotherapy in terms of tumor shrinkage, and even fewer experience long-term remission or cures as a result.

Why didn't immunotherapy live up to its hype?

It turns out that, just as cancer cells can be inherently chemoresistant or radioresistant (resistant to chemotherapy or radiation therapy) or can acquire chemoresistance or radioresistance, cancer cells can be inherently immunoresistant (resistant to immunotherapy) or can acquire immunoresistance. Also, just as there can be severe side effects with chemotherapy or radiation therapy, the same is valid for immunotherapy.

One of the potential side effects of immunotherapy is the development of autoimmune reactions.
Autoimmune side effects occur when the immune system, stimulated to fight cancer cells, mistakenly attacks healthy cells and tissues in the body. This can lead to various autoimmune-related side effects, depending on the specific type of immunotherapy used and the organs or tissues being affected.

Some common autoimmune side effects of immunotherapy include:

· Dermatologic: Skin-related side effects such as rash, itching, or dry skin can occur. In more severe cases, blistering or peeling skin may develop.
· Gastrointestinal: Immunotherapy can cause inflammation in the gastrointestinal tract, leading to symptoms such as diarrhea, nausea, vomiting, abdominal pain, and, in severe cases, colitis.
· Hepatic: Liver inflammation or hepatitis may occur, leading to elevated liver enzymes, fatigue, and jaundice. 
· Endocrine: The endocrine system can be affected by immunotherapy, resulting in hypothyroidism, hyperthyroidism, adrenal insufficiency, or type 1 diabetes.
· Pulmonary: Inflammation in the lungs, also known as pneumonitis, can cause symptoms such as shortness of breath, cough, and chest pain.
· Neurological: The nervous system may be affected, leading to side effects like headache, dizziness, muscle weakness, or more severe conditions like encephalitis or meningitis.
· Rheumatologic: Some patients may experience joint, muscle, or other rheumatologic symptoms.
· Hematologic: In rare cases, immunotherapy can lead to blood-related side effects such as anemia, thrombocytopenia, or neutropenia.

To combat immunoresistance and promote immune sensitization of cancer cells (sensitizing them to immunotherapy), and inhibit immunotherapy-induced autoimmunity, the following should be considered:

Suppression of interleukin-6 (IL-6): IL-6 is a cytokine, a type of signaling molecule produced by immune cells and other cell types in the body. IL-6 has various functions, including regulating immune responses, inflammation, and hematopoiesis (forming blood cells). In the context of tumors, IL-6 can play a significant role in promoting tumor growth, immune evasion, and cancer progression. Tumor cells and the surrounding cells in the tumour microenvironment can produce IL-6. IL-6 receptor blockade was found to increase the efficacy of immunotherapy while mitigating immunotherapy-induced autoimmunity. Compounds that have been found to inhibit IL-6 include curcumin, epigallocatechin-3-gallate (EGCG), Ganoderma lucidum (reishi mushroom), omega-3 fatty acids, quercetin, resveratrol, siltuximab, sulforaphane, and thalidomide.

Metabolic reprogramming using calorie-restriction mimetics: Calorie restriction refers to a dietary regimen that reduces calorie intake without causing malnutrition. Calorie restriction has been found to improve the function of immune cells, such as T cells and natural killer cells, and enhance their ability to target and kill cancer cells. Calorie restriction mimetics (CRMs) are compounds that can mimic physiological calorie restriction without reducing calorie intake. Examples include 2-deoxy-D-glucose, acarbose, EGCG, hydroxy citric acid, metformin, quercetin, rapamycin, and resveratrol. Emerging data has shown that using CRMs may serve as an essential adjuvant to immunotherapy.

Blocking of histamine receptor H1 (HRH1): Tumors can "polarize" cancer-killing M1 macrophages by changing them to cancer tumor-promoting and T-cell-inhibiting M2 macrophages (also known as tumor-associated macrophages or TAMs). High histamine levels in the tumor environment bind to HRH1 receptors on the surface of tumor-associated macrophages and contribute to the suppression of T-cell function, resulting in tumor resistance to immunotherapy. Antihistamines were found to block the histamine receptors on macrophages, thereby blocking their polarization from M1 to M2 macrophages, thus resulting in restored T-cell antitumor activity.

Overcoming the challenge of 'exhausted' T cells: T cells, also known as T lymphocytes, are a type of white blood cell that plays a central role in the immune system. They help protect the body against infections and diseases by recognizing and eliminating foreign invaders such as viruses, bacteria, parasites, and cancer cells. CD8+ T cells are the main "assassins" of cancer cells. They directly target and kill infected or cancerous cells by recognizing specific antigens (foreign substances) presented on the surface of these cells. Cytotoxic T cells release molecules like perforin and granzymes that induce apoptosis (programmed cell death) in the target cells.

Cancer immunotherapy depends on mobilizing T cells to target and eliminate tumor cells. T cells are not as effective against cancer as expected, however. A critical obstacle for immunotherapy is the decline in T cells' capacity to destroy, commonly known as exhaustion. Prolonged activation of the immune system, as seen in chronic viral infections or the gradual progression of cancer, or overstimulation of the immune system from immunotherapy, can cause T cells to tire and lose their effectiveness. T-cell exhaustion is a major pathway of resistance to immunotherapy.

Compounds that have been found to reinvigorate T cell function and possibly improve the efficacy of immunotherapy by sustaining the cytotoxic activity of T cells include creatine, curcumin, EGCG, Ganoderma lucidum (reishi mushroom), metformin, quercetin, resveratrol, statins, sulforaphane, thalidomide, and thymosin alpha 1 (Tα1).

Dr Daniel Thomas, DO, MS
Metabolic & Nutritional Medicine
Integrative Cancer Therapeutics
Mount Dora, Florida